Increasing evidence points to an important role of reductive stress (a decrease in free cytosolic NAD+INADH ratio) in mediating diabetes-related neural dysfunction. This Study was aimed at evaLuating the redox state of free cytosolic NAD(P)-couples and related metabolic parameters in sciatic nerve in streptozotocin-diabetic (D)and 50% galactose-fed (G) rats with durations of diabetes and galactose feeding of 2 and 10 days. Metabolite levels were assayed spectrofluorometrically in individual nerves by enzymatic procedures. Free cytosolic NAD+INADH, NADP+/NADPH ratios, and phosphate potential (ATP/ADP*Pi) were estimated from metabolites of lactate dehydrogenase, malic enzyme, and glyceraldehyde-3-phosphate dehydrogenase - 3-phosphoglycerate kinase systems. Free cytosolic NAD+INADH ratios were 701+249 for control (C), 333+140 and 5l7+213 for 2 and 10 day D (p<0.006 and <0.015 vs C), and 393+8 and 449+60 for 2 and 10 day G (p<0.006 and <0.0001 vs C). Free cytosolic NADP+/ADPH ratios and phosphate potentials were 0.048+0.012 and 1629+829 for C, 0.024+0.015 and 483+176 for 10-day D (p<0.002 and <0.003 vs C), and 0.036+0.014 and 385+101 for 1O day G (p<0.O4 and <0.002 vs C). The changes in nerve redox state and phosphate potentials were completely or partially prevented by tolrestat, an aldose reductase inhibitor (AM), at a dose of 100 mg/kg bwt/day. Cytosolic NAD+/NADH, NADP+/NADPH, and ATP/ADP*Pi were 9l1+311, 0.058 + 0.020, and 781+133 for D+ARI (p<0.002,<0.0002, and <0.04 vs D), and 63O+197, 0.O5O+.014, and 1148+392 for G+ARI (p <0.O006,<0.03. and <0.0006 vs G). These observations suggest that: 1) reductive stress is a very early metabolic imbalance in sciatic nerve in both diabetic and galactose-fed rats, and 2) aldose reductase-linked mechanisms mediate interrelated changes in the redox state of cytosolic NAD(P)-couples and phosphate potential in these animal models.